Alterations in regulation of energy homeostasis in cyclic nucleotide phosphodiesterase 3B–null mice
Young Hun Choi, … , Eva Degerman, Vincent C. Manganiello
Young Hun Choi, … , Eva Degerman, Vincent C. Manganiello
Published December 1, 2006
Citation Information: J Clin Invest. 2006;116(12):3240-3251. https://doi.org/10.1172/JCI24867.
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Research Article Metabolism

Alterations in regulation of energy homeostasis in cyclic nucleotide phosphodiesterase 3B–null mice

Abstract

Cyclic nucleotide phosphodiesterase 3B (PDE3B) has been suggested to be critical for mediating insulin/IGF-1 inhibition of cAMP signaling in adipocytes, liver, and pancreatic β cells. In Pde3b-KO adipocytes we found decreased adipocyte size, unchanged insulin-stimulated phosphorylation of protein kinase B and activation of glucose uptake, enhanced catecholamine-stimulated lipolysis and insulin-stimulated lipogenesis, and blocked insulin inhibition of catecholamine-stimulated lipolysis. Glucose, alone or in combination with glucagon-like peptide–1, increased insulin secretion more in isolated pancreatic KO islets, although islet size and morphology and immunoreactive insulin and glucagon levels were unchanged. The β3-adrenergic agonist CL 316,243 (CL) increased lipolysis and serum insulin more in KO mice, but blood glucose reduction was less in CL-treated KO mice. Insulin resistance was observed in KO mice, with liver an important site of alterations in insulin-sensitive glucose production. In KO mice, liver triglyceride and cAMP contents were increased, and the liver content and phosphorylation states of several insulin signaling, gluconeogenic, and inflammation- and stress-related components were altered. Thus, PDE3B may be important in regulating certain cAMP signaling pathways, including lipolysis, insulin-induced antilipolysis, and cAMP-mediated insulin secretion. Altered expression and/or regulation of PDE3B may contribute to metabolic dysregulation, including systemic insulin resistance.

Authors

Young Hun Choi, Sunhee Park, Steven Hockman, Emilia Zmuda-Trzebiatowska, Fredrik Svennelid, Martin Haluzik, Oksana Gavrilova, Faiyaz Ahmad, Laurent Pepin, Maria Napolitano, Masato Taira, Frank Sundler, Lena Stenson Holst, Eva Degerman, Vincent C. Manganiello

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Figure 6

Differences in insulin secretion from pancreatic islets, serum insulin concentrations, and blood glucose disposal in WT and Pde3b-KO mice.

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Differences in insulin secretion from pancreatic islets, serum insulin c...
(A) Insulin accumulation during incubation of isolated pancreatic islets for 1 hour with 3 or 16.7 mM glucose and without or with 100 nM GLP-1 as indicated. Data are mean ± SEM (n = 4). Inset: Immunoreactive PDE3B was detected by Western blots of WT, not KO, homogenates. (B) CL (1.0 mg/kg) in PBS or PBS alone was injected i.p. (10 ml/kg) into 6-month-old WT and KO mice. At the indicated times, differences from time 0 (basal) in serum insulin levels were quantified. Basal insulin levels in WT and KO mice were 1.4 ± 0.2 and 2.6 ± 0.1 ng/ml, respectively. Data (mean ± SEM; n = 4 mice per group) are representative of 3 experiments. (C and D) ISO or CL (1.0 mg/kg) in PBS or PBS alone were injected i.p. or i.v. (10 ml/kg) into 3- (i.p) or 4-month-old (i.v.) WT and KO mice. After 20 minutes, tail blood was collected, and changes from basal serum insulin (C) and blood glucose (D) levels were measured. Basal values were similar in PBS-treated WT and KO mice. Data (mean ± SEM; n = 4–5 mice per group) are representative of 3 experiments. *P < 0.05; **P < 0.01; †P < 0.001.